Pharmacology I: Beta-Lactam Antibiotics PDF

PM 716 Pharmacology I Chapter 43 Beta Lactams RMRocco, PhD PM 716 C43 Beta Lactams 1  Beta Lactam Antibiotics Alexander Fleming (1881-1955) On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenza...

PM 716 Pharmacology I Chapter 43 Beta Lactams RMRocco, PhD PM 716 C43 Beta Lactams 1  Beta Lactam Antibiotics Alexander Fleming (1881-1955) On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae. British J. Exp Pathology 10:226-236 (1929). PM 716 C43 Beta Lactams 2 Alexander Fleming (1881-1955) PM 716 C43 Beta Lactams 3  Penicillium Mold World’s first antibiotic (from nature) which led to wide range of penicillins and cephalosporins. All inhibit bacterial cell wall synthesis PM 716 C43 Beta Lactams 4  The Oxford Group E. Chain, H. W. Florey, A. D. Gardner, N. G. Heatley, M. A. Jennings, J. Orr-Ewing, A. G. Sanders. Penicillin as a chemotherapeutic agent. Lancet ii:226-228 (1940) PM 716 C43 Beta Lactams 5 Penicillin First antibiotic from a mold or living species. Fleming, Florey and Chain share Nobel Prize in 1945. Widespread use in WWII. PM 716 C43 Beta Lactams 6 Penicillin First treated patient Feb 12, 1941, London Ann Miller, New Haven, CT. March 14, 1942. Drug from Florey in England. Used to treat burn patients from Cocoanut Grove Fire, Nov 28, 1942. PM 716 C43 Beta Lactams 7 Penicillin Beta lactam ring required for binding site to bacterial cell wall. Thiazolidine ring provides pharmacokinetic properties. PM 716 C43 Beta Lactams 8  Penicillin Units Used historically for any drug which has yet to be isolated in pure form. Drug “weight” provided in Units defined in terms of biological potency. Often when purity and/or synthesis has been achieved the older Unit system discarded. 1 mg penicillin = 1600 Units PM 716 C43 Beta Lactams 9  Mechanism of Action Beta lactams bind to a Penicillin Binding Protein (PBP) found in the cell walls of bacteria. PBP contains a transpeptidase enzyme which is inhibited by beta lactams. Cell wall synthesis is inhibited. PM 716 C43 Beta Lactams 10  Mechanisms of Resistance 1. Some bacteria contain intrinsically structurally different PBP. 2. Bacteria develop high-mol weight PBP with decreased affinity for antibiotic. 3. Bacteria develop efflux pumps that keep out antibiotic. 4. Bacteria make beta lactamse which destroys antibiotic. Gram Pos very common. Less so with Gram Neg. PM 716 C43 Beta Lactams 11  Mechanisms of Resistance Resistance first reported in 1944 (two years after being introduced). 1950, 50% of all isolates in US are resistant. 1960 methicillin introduced 1993 Japan reports 60% isolates are methicillin resistant 1995 vancomycin iv only solved problem. Nine genes required to overcome vanco. 1998 15% of all Enterococci now resistant to vancomycin. PM 716 C43 Beta Lactams 12 Beta Lactamase Opens beta lactam ring structure and removes all antibiotic activity. PM 716 C43 Beta Lactams 13 Monobactams Sulbactam derivatives. Beta-lactamase inhibitors: sulbactam, clavulanic acid, tazobactam. PM 716 C43 Beta Lactams 14  Clavulanic acid Augmentin® (amoxicillin + clavulanic acid) PM 716 C43 Beta Lactams 15  Beta Lactamase Inhibitors Clavulanic acid, sulbactam, tazobactam Weak to no antibiotic activity on their own. All used to inhibit beta lactamase. Available only in combination with one of the penicillin drugs. Not specific for all beta lactamases. Serratia produces a beta lactamse not inhibited by sulbactam for example. PM 716 C43 Beta Lactams 16 Chapter 43 Beta-Lactam & other Cell Wall- & Membrane- Active Antibiotics PM 716 C43 Beta Lactams 17 © The McGraw-Hill Companies, Inc,  Penicillin Groups 1. Penicillins Pen G Group. Gram Pos cocci and non-beta lactamase producing bacteria. 2. Beta lactamase resistant penicillins. Nafcillin. Oxacillin. Cloxacillin for S aureus, S. epidermidis. 3. Extended spectrum penicillins. Ampicillin Amoxicillin for Gram Neg. Haemophilus influenzae, E. coli, Proteus mirabilis. Hydrolyzed by beta lactamase. PM 716 C43 Beta Lactams 18  Penicillin Groups 4. Cabenicillin, Ticarcillin for Listeria, Proteus, Enterobacter and Pseudomonas. 5. Mezlocillin, Azlocillin and Piperacillin for Pseudomonads, Klebsiella and some Gram Neg. 6. (See pg 5 in the Handouts for all required drugs for this chapter). PM 716 C43 Beta Lactams 19 Chapter 43 Beta-Lactam & other Cell Wall- & Membrane- Active Antibiotics PM 716 C43 Beta Lactams 20 © The McGraw-Hill Companies, Inc,  Pharmacokinetics Absorption varies among different penicillins. Drugs blocked by food, administer 1-2 before or after meals (drug binds to food). Benzathine and procaine penicillins have delayed absorption after im injection. Drugs mostly cleared unmetabolized through kidney. PM 716 C43 Beta Lactams 21  Clinical Uses Pen G (iv form) drug of choice for streptococci, meningococci, enterococci, penicillin-susceptible penumococci, non- beta-lactamase producing staphylococci, Treponema pallidum, other Gram Pos rods, and non beta lactamase producing Gram Neg anaerobes. PM 716 C43 Beta Lactams 22  Clinical Uses Pen V (oral form) used for minor infections due to low F and 4x per day dosing. Amoxicillin used instead. Methicillin, nafcillin used for beta lactamase producing staphylococci. Extended spectrum penicillins (aminopenicillins, carboxypenicillins) Similar to Pen G but better Gram Neg due to ability to penetrate the outer plasma type membrane. PM 716 C43 Beta Lactams 23  Adverse Reactions Safe drugs with hypersensitivity as most common ADR. About 5 -8 % patients claim sensitivity. Less than 1% of patients who received drugs will have reaction with second exposure. PM 716 C43 Beta Lactams 24  Allergic Reactions Anaphylactic shock: ~ 0.05 % patients on the drug. (10 -40/100 000 receiving drug) Penicillin accounts for 75% of deaths from anaphylactic shock in the US. Allergic reactions complicate up to 4% of all treatment courses. PM 716 C43 Beta Lactams 25  Allergic Reactions Found with most in the penicillin group. Reactions include: rash. Fever, bronchospasm, vasculitis, serum sickness, dermatits, anaphylaxis. Exposure to drugs in food may result in first sensitizing exposure. Allergy may occur when beta lactam ring is opened and penicilloyl moiety binds to protein and forms a hapten. PM 716 C43 Beta Lactams 26  Penicillin G Pen G and Pen V are called “natural” penicillins because they are harvested from mold cultures. The G and V are old terms which designated their source cultures. Pen G is for im and iv Pen V used po. PM 716 C43 Beta Lactams 27 Penicillin Penicillin G benzylpenicillinic acid Penicillin V phenoxymethylpenicill in PM 716 C43 Beta Lactams 28  Pencillin G Drug of choice for streptococcal infections. (1 million units = ~ 600 mg) DOSE: up to 20 million units/day iv with lower doses im. PM 716 C43 Beta Lactams 29 Penicillin G Penicillin G Procaine The addition of procaine prolongs serum levels up to 12 h post im dose Penicillin G Benzathine prolongs levels up to 1 month. PM 716 C43 Beta Lactams 30 Penicillin with Probenecid Concomitant administration of probenecid up to 1-2 g/day will increase and prolong serum penicillin levels. Drug slows secretion of penicillin from renal proximal tubule. PM 716 C43 Beta Lactams 31  Penicillin G Uses limited because of short half life and resistance. Cellulitis from Gram pos cocci chains Osteomyelitis due only to streptococci Gas gangrene (Clostridial cellulitis) Dose adjustment required when CC below 30 -50 mL/min range. PM 716 C43 Beta Lactams 32 Ampicillin Developed to increase Gram neg coverage. High rates of resistance. Used iv, im and po. Properties similar to Penicillin. PM 716 C43 Beta Lactams 33 Ticarcillin (Ticar©) More active against Pseudomonas than others in penicillin category. Not active against staph. IV or IM. Requires dosage adjustment when CC below 60 mL/min. PM 716 C43 Beta Lactams 34  Beta Lactamase Inhibitor Combinations Amoxicillin/Clavulanic Acid (and others) Various weight tablets all with 125 mg clavulanic acid. Note Amox/Clavulanic acid combinations 250/125 500/125 875//125 two 250/125 = 500/250 mg one 500/125 = 500/125 mg PM 716 C43 Beta Lactams 35  Combinations Used when Gram neg organism produces plasmid-mediated beta-lactamase enzyme Useful for diabetic foot ulcers and mixed organism skin infections. Drug of choice for emperical treatment of animal bite wounds. PM 716 C43 Beta Lactams 36  MRSA Methicillin Resistant staphylococcus aureus (MRSA) now found in hospitals and in the community. S. aureus is normal on skin but can cause infections from pimples, boils, pneumonia and blood infections. S. aureus (not MRSA) most common cause of skin and soft tissue infection in the US. PM 716 C43 Beta Lactams 37  MRSA Cause of increase in MRSA might be due to extensive use of third-generation cephalosporins and/or widespread use of quinolones. Vancomycin and linezolid usual drugs of choice. TMP/SMX also used. PM 716 C43 Beta Lactams 38  MRSA S. aureus patterns of resistance: (a) Less than 5% of all isolates sensitive to penicillins. (non lactamase producers) (b) Methicillin sensitive, produce lactamase. (c) MRSA through chromosmal mutation of PBP to PBP-2a. Non lactamase producers. Resistant to all beta lactams. (d) Vancomycin Intermediate, MIC = 8 ug/mL. PM 716 C43 Beta Lactams 39  Antibiotics Cell Wall Inhibitors I Penicillins penicillin G carbenicillin piperacillin penicillin V dicloxacillin amoxicillin nafcilin ampicillin oxacillin ticarcillin methicillin Combination Penicillins amoxicillin/clavulanic acidpenicillin G procaine ticarcillin/clavulanate penicillin G benzathine ampicillin/sulbactam PM 716 C43 Beta Lactams 40  Antibiotics Penicillin with added components procaine probenecid benzathine PM 716 C43 Beta Lactams 41 Cephalosporins Discovered on the Italian island of Sardinia. Isolated from a mold growing in the sewage outflow. PM 716 C43 Beta Lactams 42 Giuseppe Brotzu (1895-1976) Discovers the first cephalosporin in July 1945. Publishes the first report in 1948 “These findings have been reported here in the hope that other better equipped institutes may be able to make greater progress in the..........preparation and extraction of the antibiotic.” PM 716 C43 Beta Lactams 43 Penicillin vs Cephalosporin dihydrothiazine ring thiazolidine ring PM 716 C43 Beta Lactams 44 Cephalosporins First isolated from cephalosporin fungus in 1948. Mostly resistant to beta lactamase. PM 716 C43 Beta Lactams 45 Chapter 43 Beta-Lactam & other Cell Wall- & Membrane- Active Antibiotics PM 716 C43 Beta Lactams 46 © The McGraw-Hill Companies, Inc,  Cephalosporins Gram Pos Gram Neg 1st Gen Most None (Staph, Strep) 2nd Gen Most Some (Haemophilus) 3rd Gen Some All 4th Gen All All PM 716 C43 Beta Lactams 47  Cephalosporins 1st cefazolin cephradine cephalexin cefadroxil 2nd cefamandole cefaclor cefotetan cefoxitin (iv, im) 3rd cefoperazone cefotaxime ceftazidime (iv) (iv, im) (iv, im) 4th cefepime (iv) PM 716 C43 Beta Lactams 48 Chapter 43 Beta-Lactam & other Cell Wall- & Membrane- Active Antibiotics PM 716 C43 Beta Lactams 49 © The McGraw-Hill Companies, Inc,  Additional Classification Items All first generations are effective against Gram Pos cocci. Second generation developed for H. influenzae and are effective against additional Gram Neg (Proteus, E. coli). Third generation developed for “nosocomials” but resistance has reduced usefulness. Fourth generation has both Gram Pos and Gram Neg including P. aeruginosa. PM 716 C43 Beta Lactams 50  First Generation First Generation Staphylococci (beta lactamase Pos and Neg) Streptococci Gram Neg (E. coli, P. mirablis, Shigella, Salmonella). Anaerobes (not Bacteroides) PM 716 C43 Beta Lactams 51  First Generation More resistant to beta lactamase. Variable oral F, excretion mainly kidney Adjust dose for renal function (CC) Probenecid used to block tubular secretion and increase Cp levels. IN TABLE: Only cefazolin is parenteral, remainder are given po. PM 716 C43 Beta Lactams 52 First Generation Cefazolin (Ancef® and others) Typical Dose: 1 g q8h im or iv. Dose reduction required for CC decrease. PM 716 C43 Beta Lactams 53  Second Generation Second Generation Staphylococci Streptococci Expanded Gram Neg (resistant E. coli, H. influenzae) Anaerobes with some Bacteroides. PM 716 C43 Beta Lactams 54  Second Generation cefamandole , cefoxitin Extended coverage of Gram Neg compared to First Generation Klebsiellae, H. influenzae All Second Gen are less active against Gram Pos compared to First Genration Active against beta lactamase Pos H. influenzae and Klebsiella pneumoniae. Also, anaerobes (B. fragilis) PM 716 C43 Beta Lactams 55 Bacteroides fragilis Gram neg anaerobe rods 12 year old boy with jaw infection (without bone involvement). PM 716 C43 Beta Lactams 56  Third Generation Third Generation Staphylococci (less active than older generations) Streptococci Good activity against Gram Neg rods Good gonococci coverage Anaerobes similar to other generations, Bacteroides varies. PM 716 C43 Beta Lactams 57  Third Generation Cefoperazone, ceftriaxone, cefotaxime. Expand spectrum for Gram Neg Some drugs cross the BBB (used for meningitis) Active against citrobacter, Serratia marcescens, beta lactamase Pos Haemophilus and neisseria. Drug of choice for gonorrhea. PM 716 C43 Beta Lactams 58  Fourth Generation Fourth Generation Staphylococci Streptococci Gram Neg including P. aeruginosa. PM 716 C43 Beta Lactams 59  Fourth Generation Cefepime Good for beta lactamse Pos which do not respond to Third Generation. Used for P. aeruginosa, enterobacteriaceae, S. aureus, S. pneumoniae, haemophilus, neisseria. Crosses the BBB well Good for penicillin resistant strains of streptococci. General clinical use similar to Third Generation. PM 716 C43 Beta Lactams 60 Fourth Generation Cefepime (Maxipime®) Dose: 1-2 g q12h iv Very broad spectrum cephalosporin used in mixed infections. PM 716 C43 Beta Lactams 61  Antibiotics Other Cell Wall Inhibitors vancomycin: cyclic peptide bacitracin: cyclic peptide, gram pos, topical only daptomycin: cyclic peptide PM 716 C43 Beta Lactams 62 Vancomycin PM 716 C43 Beta Lactams 63  Vancomycin Results of an extensive search in the 1950’s for a drug to treat penicillin-resistant staphylococci. Produced by Streptomyces orientalis bacterium. Organism isolated from a soil sample from Borneo that was sent to Eli Lilly (Indianapolis) for isolation and study. Vancomycin named from word “vanquish” because it worked with resistant staph. PM 716 C43 Beta Lactams 64  Vancomycin FDA Approved in the US 1958. Mechanism of action is to inhibit biosynthesis of cell wall peptidoglycans. Mechanism of action different from Beta Lactams. PM 716 C43 Beta Lactams 65  Vancomycin vs Cephalosporins LD50 in mice mg/Kg iv dosing penicillin G 3040 mg cefoxitin 7950 mg vancomycin 400 mg PM 716 C43 Beta Lactams 66  Vancomycin Inhibits cell wall synthesis Produced by Streptococcus orientalis. Polypeptide with mw 1500 Gram Pos only (especially Staph) Drug binds to the D-Ala-D-Ala terminus of peptidoglycan pentapeptide preventing further elongation of the peptide chain. PM 716 C43 Beta Lactams 67  Vancomycin Poorly absorbed in GI (polypeptide). Dose is iv. S. aureus stain resistant to vancomycin identified in Japan in 1996. Vancomycin resistant enterococci makes these infections incurable. PM 716 C43 Beta Lactams 68  Drug Levels vs Time Profile iv po po controlled Cp release Time PM 716 C43 Beta Lactams 69  Vancomycin Monitoring Cp levels during therapy Peak Cp 20-40 ug/mL Trough Cp 5-10 ug/mL Toxic Cp > 80 ug/mL PM 716 C43 Beta Lactams 70  Vancomycin Pharmacokinetics Following a single iv dose infused over 4 minutes in patients with normal CC, the average Cp levels are 1 min 33 ug/mL 1 hour 7.3 ug/mL 24 hours 2.8 ug/mL PM 716 C43 Beta Lactams 71  Plasma Monitoring Peak Cp levels to determine max allowable concentration and to minimize toxicity. Trough Cp levels to ensure that the dose has cleared before the next dose administered. This helps prevent accumulation and toxicity. Adjustments in dose required for decreased CC levels. PM 716 C43 Beta Lactams 72  Vancomycin Distribution following iv dosing into synovial fluid is almost equal to the concentration in plasma. This makes direct injection into infected joints unnecessary. Clearance is mostly through kidney and dose adjustment required for decreased CC rates. PM 716 C43 Beta Lactams 73  Vancomycin ADRs ADRs have been reduced over the years as the commercial preparations became more pure. “Red Man Syndrome” a rash or flushing of the face and neck due to histamine release. Incidence decreased with low dose (1 g) and slow infusion (1 g over 12 hours). Ototoxicity and nephrotoxicity may have been due to drug impurities. Incidence redueced ( 32 ug/mL Cp > 40 ug/mL possible toxicity. Damage to 8th cranial nerve, deafness. PM 716 C43 Beta Lactams 78  Vancomycin Pharmacokinetics Following a single iv dose infused over 4 minutes in patients with normal CC, the average Cp levels are 1 min 33 ug/mL 1 hour 7.3 ug/mL 24 hours 2.8 ug/mL PM 716 C43 Beta Lactams 79  Vancomycin Monitoring Cp levels during therapy Peak Cp 20-40 ug/mL Trough Cp 5-10 ug/mL (Do not administer next iv dose if trough is above 10 ug/mL). Toxic Cp > 80 ug/mL PM 716 C43 Beta Lactams 80 Bacitracin PM 716 C43 Beta Lactams 81  Bacitracin Produced by Bacillus subtilis Effective against most Gram Pos and some Gram Neg organisms. Available for im (limited use) and for topical OTC use. PM 716 C43 Beta Lactams 82 Chapter 43 Beta-Lactam & other Cell Wall- & Membrane- Active Antibiotics PM 716 C43 Beta Lactams 83 © The McGraw-Hill Companies, Inc,  Case Study 55 year-old male, three day fever and productive cough. Patient takes hydrochlorothiazide and lisinopril for hypertension and is allergic to amoxicillin (developed a rash in the past). Chest film shows left lung pneumonia. Possible meningitis, need a drug to treat both and avoid allergy. PM 716 C43 Beta Lactams 84  Case Study Third generation cephalosporin (ceftriaxone) that penetrates into CNS and active against common pneumonia bacteria. Vancomycin in case pneumococcus is resistant. Rash from amoxicillin is not consistent with anaphylaxis, probably OK to use a ceph. Re-adjust after C&S results come back from the lab. PM 716 C43 Beta Lactams 85